Asymmetric synthesis of 3-substituted furanoside compounds

ABSTRACT

Novel processes, intermediates and reagents for the preparation of 3-substituted furanose or furanoside compounds of Formula I: &lt;CHEM&gt; wherein M is hydrogen or alkyl (C&lt;5&gt;-C&lt;7&gt;), A is halogen or A may be selected from a moiety of the formula: OR, SR, N&lt;7&gt;, SCR, OC-R or CN wherein R is hydrogen, branched or unbranched alkyl (C&lt;5&gt;-C&lt;8&gt;) or phenyl which compounds have antiviral and other biological activity.

FIELD OF THE INVENTION

The present invention is directed to novel processes, intermediates andreagents for the preparation of 3-substituted furanose or furanosidecompounds useful as intermediates in the synthesis of various modifiednucleosides having biological activity.

BACKGROUND OF THE INVENTION

The recent discovery of the reverse transcriptase inhibiting activity ofvarious modified nucleosides and their actual and potential utility astherapeutic agents in the treatment of Acquired ImmunodeficiencySyndrome (AIDS) related human immunodeficiency virus (HIV) infections,has stimulated interest in improved methods of preparing such modifiednucleosides. Of particular interest are new methods of preparing3-substituted 2',3'-dideoxyribonucleosides such as3'-azido-3'-deoxythymidine (AZT) and 3'-deoxy-3'-fluorothymidine (FLT)which have been reported to be potent inhibitors of HIV-inducedcytopathogenicity. Extensive studies on the synthesis and biologicalactivity of 3'-azido, 3'-amino, and 3'-fluoro pyrimidine and purine2',3'-dideoxyribonucleoside analogues have been reported.

In general, methods of producing such 3'-substituted nucleosides haveproceeded along two separate paths: (1) substitution of the 3'-OHfunction in a 2'-deoxynucleoside, as in the case of the synthesis of AZTor FLT from thymidine, or (2) preparation of a 3-substituted furanosidecompound followed by the coupling of a suitable purine or pyrimidinebase such as thymine. The latter method has certain advantages since ituses simpler starting materials and it provides for the easysubstitution of a number of nucleophiles at the 3'-position to provideintermediates suitable for efficient coupling with purine or pyrimidinebases. The latter method therefore provides the greatest possibilitiesfor synthesis of 3'-substituted nucleosides in the large scalequantities.

Several methods for the synthesis of 3-substituted furanoside sugarshave been described, but they are complicated, and they require multiplesteps and expensive reagents. Fleet, G. W. et al; Tetrahedron 1988,44(2) 625-636 describes the synthesis of methyl5-O-tert-butyldiphenylsilyl-2-deoxy-α(β)-D-threo-pentofuranoside fromD-xylose and its conversion to the azido, fluoro and cyano sugarsfollowed by the subsequent coupling of these derivatives with protectedthymine to give the thymidine compounds. Bravo, P. et al., J. Org. Chem.1989, 54, 5171-5176 describes the asymmetric synthesis of the3-fluorofuranoses starting from a compound of the formula: ##STR2##which is monoalkylated on the fluorinated carbon with allyl bromide.Removal of the auxiliary sulfinyl group followed by a reductive work-upand oxidative cleavage of the double bond afforded the5-O-benzoyl-2,3-dideoxy-3-fluorofuranose.

The present invention describes and improved alternate method for thesynthesis of the 3-substituted furanoses and furanosides. The process ifuncomplicated, uses a small number of steps and simple, inexpensivestarting materials.

SUMMARY OF THE INVENTION

This invention is an improved process for the asymmetric synthesis of3-substituted furanoside compounds of the formula: ##STR3## wherein M ishydrogen or alkyl (C₁ -C₃), A is halogen or A may be selected from amoiety of the formula: OR, SR, N₃, ##STR4## or CN wherein R is hydrogen,branched or unbranched alkyl(C₁ -C₄) or phenyl. The improved process maybe depicted by the following reaction Scheme I: ##STR5##

In the foregoing Scheme I, X may be chloride or bromide.

The present invention is also directed to a novel process of preparingfluorinating reagents of the formula:

    Ti(OR').sub.n A.sub.4-n

wherein n is an integer from one to three, R' is branched or unbranchedalkyl (C₁ -C₄) and A is as defined above.

DETAILED DESCRIPTION

In accordance with Scheme I, propargyl alcohol 1 is reacted with allylchloride or allyl bromide 2 to afford alcohol 3. Reduction of 3 withlithium aluminum hydride yields olefin 4. Epoxidation of 4 gives oxirane5. Regioselective oxirane ring opening of 5 by treatment with anappropriate nucleoplilic reagent having the substituent A gives diol 6which is treated with ozone and then hydrogenated in the presence of 10%palladium on carbon to give the substituted pentose compound of formula7.

In the preferred embodiment of the present invention, the 3-substitutedfuranoside sugars of Formula I are prepared by the following steps:

(a) Propargyl alcohol 1 is condensed with allyl chloride or allylbromide 2 in water at pH 8-9 at a temperature of 65°-70° C. understirring with CuCl or CuBr to yield hex-5-en-2-yn-1-ol 3;

(b) Compound 3 is then reduced by LiAlH₄ in tetrahydrofuran to yield theallyl alcohol, 4, trans-2,5-hexadien-1-ol;

(c) the allyl alcohol 4 is then asymmetrically epoxidized in thepresence of diisopropyl-D-(-)-tartrate to yield the oxirane compound 5,2R,3R-epoxyhex-5-en-1-ol;

(d) the oxirane compound 5 is then subjected to regioselectivenucleophilic ring opening by treatment with an appropriate nucleoplilicreagent of the formula:

    Ti(OR').sub.n A.sub.4-n

wherein n is an integer from 1 to 3, R' is branched or unbranchedalkyl(C₁ -C₄) and A is as defined above to yield the diol compound offormula 6;

(e) the diol compound 6 is then subjected sequentially to

i) ozone;

ii) reductive workup by hydrogenation with H₂ on palladium-on-carbonand;

iii) alcoholysis to yield 3-substituted-2,3-dideoxy-D-erythropentosidesof formula 7, as a mixture of α and β isomers.

As set forth above in step (c), the allyl alcohol compound 4 isasymmetrically epoxidized by the method of Y. Gao et al., J. Amer. Chem.Soc., 109, 5765-5780 (1987), hereby incorporated by reference into thepresent application. This method produces epoxides from olefins in atleast a 94% enantiomeric excess. Olefins can be converted to thecorresponding epoxide on treatment with a catalytic amount of a catalystprepared from a tartrate such as diethyl or diisopropyl tartrate andtitanium (IV) isopropoxide. The best ratio of titanium/tartrate is1:1.2. It is important to keep the reaction mixture free of moisture.Powdered activated molecular sieves work well. Solvents such asdichloromethane, toluene or isooctane can be used. Reactions aregenerally carried out at temperatures of about 31 20° C. All reactionsare done in the presence of tert-butyl hydroperoxide (TBHP), althoughother peroxides may be used.

In general, the tartrate catalyst is prepared by mixing the chosentartrate and titanium (IV) isopropoxide at -20° C. in a solvent such asmethylene chloride whereupon either the olefinic alcohol or thetert-butyl hydroperoxide is added. In any case, the three ingredientsare added and stirred for about 30 minutes before the last reagent isadded whether it be the alcohol or the tert-butyl hydroperoxide. Allreactions are carried out in the presence of powdered activated sieves.The 30 minutes of stirring is termed the "aging" period and is animportant factor in obtaining high enantioselectivity.

In step (d) above, the oxirane compound 5 is subjected to regioselectivenucleophilic ring opening by mild treatment with a reagent of theformula:

    Ti(OR').sub.n A.sub.4-n

wherein n is an integer from 1 to 3, R' is branched or unbranched alkylof 1 to 4 carbon atoms and A is defined above to yield the diol compoundof formula 6.

The nucleophilic reagents of the formula Ti(OR')_(n) A_(4-n) mayconveniently be prepared from titanium (IV) alkoxides of the formulaTi(OR')₄ by reaction with an appropriate molar concentration of thecorresponding acid, anhydride or trimethylsilyl ether compounds asfollows:

    Ti(OR').sub.4 +R"A→Ti(OR').sub.n A.sub.4-n +R"(OR').sub.4-n

where R" is hydrogen, CH₃ CO, benzoyl or Si(CH₃)₃. For example titaniumtriisopropoxy chloride may be obtained by reacting titanium (IV)isopropoxide with trimethylsilylchloride. Titanium trisopopylazide maybe obtained from titanium (IV) isopropoxide by reaction with HN₃ inpentane. Titanium triisopropyl thiobenzoate may be obtained by reactingtitanium (IV) isopropoxide with thiobenzoic acid.

The preferred nucleophilic reagent, in the case where A is fluorine, istitanium (IV) difluorodiisopropoxide, [TiF₂ (OiPr)₂ ], which canconveniently be prepared by adding titanium (IV) isopropoxide at 20°-25°C. to benzoyl fluoride or CH₃ COF in hexanes. The product, titanium (IV)difluorodiisopropoxide, is collected by filtration in an inertatmosphere.

Where the substituent A is other than fluoride, the preferrednucleophilic reagent for the ring opening reaction is titanium (IV)triisopropoxide. This reagent was used for the regioselective ringopening of the epoxide compound of the formula: ##STR6## under thereactions conditions set forth in Table I:

                  TABLE 1                                                         ______________________________________                                        Regioselective ring opening of                                                1,1-diethoxy-3R,4R-epoxypentane-5-ol by (i-PrO).sub.3 TiA                     Reaction                  Composition of the                                  Conditions                resulting mixture, %                                A      t/h     solvent  Yield, %.sup.b                                                                        (2)     (3)                                   ______________________________________                                        OAc    1       CHCl.sub.3                                                                             95      >98     <2                                    OTol   1       CHCl.sub.3                                                                             90      >98     <2                                    Cl     1       C.sub.6 H.sub.6                                                                        85      >85      15                                   SCOPh  1       CHCl.sub.3                                                                             80      >98     <2                                    N.sub.3                                                                                1.5   CHCl.sub.3                                                                             95      >92      8                                    ______________________________________                                         .sup.b A summary yield of the 3 and 4substituted acetals after the workup

The foregoing reaction conditions are equally applicable for theregioselective ring opening of compound 5, 2R,3R-epoxyhex-5-en-1-ol.Thus, the titanium (IV) triisopropoxide compounds make it possible toprovide for mild regioselective oxirane ring opening by the nucleophilicgroup A with high efficiency. This method may be used for a wide varietyof oxirane ring opening reactions where A is any nucleophilic group.

The nucleophilic ring opening reaction (step d) may be carried out in avariety of solvents including benzene, toluene, chloroform, methanol ora mixture thereof. Generally, a 1.5 mol excess of the reagent ispreferable. Temperature conditions may range from 0°-130° C. with thepreferred temperature being 80°-120° C. where the reaction generallyproceeds in less than one hour to greater than 90 percent conversion.Final products may be isolated from the reaction mixture bychromatography.

In Step (e) above, the diol compound of formula 6 is dissolved in methylalcohol and while cooling at -α° to -70° C. dry ozone is added through abubbler until the reaction is complete. After warming to 0° C.,palladium-on-carbon is added and the reaction subjected to an atmosphereof hydrogen until uptake is complete. The addition of hydrochloric acidcompletes the glycosidation to yield the3-substituted-2,3-dideoxy-erythropentose compound of formula 7, as amixture of α and β isomers.

Upon further study of the specification and appended claims, furtherobjects and advantages of this invention will become apparent to thoseskilled in the art.

This invention will be described in greater detail in conjunction withthe following, non-limiting specific examples.

EXAMPLE 1 Hex-5-en-2-yn-1-ol

To a stirred mixture of 250 ml of saturated sodium chloride solution, 1ml of hydrochloric acid, 8 g of copper (I) chloride and 28 g ofpropargyl alcohol is added at room temperature a 40% sodium hydroxidesolution until the pH is adjusted to 9. The reaction mixture is heatedin a bath of 70° C. and a solution of 120 ml of allyl chloride in 80 mlof methyl alcohol added dropwise. The pH of the reaction mixture iscarefully maintained between 8 and 9 by the coaddition of 40% sodiumhydroxide, as needed. Following complete addition of the allyl chloridesolution and with the pH between 8-9 the reaction mixture is stirred at70° C. for 3.5 hours. The flask is cooled to room temperature andhydrochloric acid added until the pH is 2. The organic phase isseparated and the aqueous layer extracted with 3×50 ml of ether. Theorganic layers are combined and the volatiles removed in vacuo to affordan oil which is vacuum distilled to yield 45 g of the desired product asa water white liquid, BP 67°-68° C./10 mm n_(D) ²⁰ 1.4670.

¹³ C-NMR: 137.69(C-5), 115.98(C-6), 82.65 and 81.54(C-2 and C-3),50.59(C-1), 23.21(C-4).

Anal. Calc'd for C₆ H₈ O: C, 74.97; H, 8.39 Found: C, 75.11; H, 8.18.

EXAMPLE 2 Trans-2,5-hexadien-1-ol

To a stirred mixture of 3.8 g of lithium aluminum hydride in 150 ml oftetrahydrofuran, cooled to 0° C. is added dropwise a solution of 9.6 gof the product of Example 1 in 50 ml of tetrahydrofuran. Followingcomplete addition the cooling is removed and the temperature allowed toreach room temperature followed by an additional 30 minutes of stirring.The temperature is raised to 45° C. for an additional 3 hours followedby cooling to 0° C. A 100 ml volume of saturated ammonium chloride iscarefully added dropwise and the resulting mixture filtered. The filtercake is washed with 3×20 ml of diethyl ether and the combined filtratedried over MgSO₄. The volatiles are removed in vacuo to a residue whichis vacuum distilled to afford 7.9 g of the desired product as a waterwhite liquid, BP 70°-72° C./15 mm, n_(D) ²⁰ 1.4530. ¹³ C-NMR:137.57(C-5), 132.01 and 128.89(C-2, C-3), 115.40(C-6), 63.00(C-1),36.80(C-4).

Anal. Calc'd for C₆ H₁₀ O: C, 73.43; H, 10.27. Found: C, 72.98; H,10.01.

EXAMPLE 3 2R,3R-Epoxyhex-5-en-1-ol

A mixture of 3.0 g of 4A powdered, activated molecular sieves and 300 mlof dry methylene chloride is cooled to -20° C. and 2.81 g (2.36 ml) ofdiisopropyl D-(-)-tartrate and 2.84 g (2.36 ml) of titanium (IV)isopropoxide added sequentially with continued stirring. The reactionmixture is stirred at -20° C. as 40 ml of 5 M TBHP in methylene chlorideis added over 5 minutes. Stirring is continued at -20° C. for 30 minutesfollowed by the dropwise addition of a solution of 9.8 g of the productof Example 2 in 50 ml of methylene chloride while keeping the reactiontemperature between -25° and -20° C. The mixture is stirred for 8-10hours at -25° to -20° C., followed by quenching with 8 ml of a 10%aqueous solution of sodium hydroxide saturated with sodium chloride (10g NaCl+10 g NaOH+95 ml of water), previously cooled to -20° C. Ether isadded to afford a 10% V/V reaction mixture. The cooling bath is removedand the stirring reaction mixture allowed to warm to 10° C. followed byan additional 10 minutes of stirring. While stirring, 8 g of magnesiumsulfate and 1 g of diatomaceous earth is added. Stirring is continuedfor an additional 15 minutes followed by filtering through a pad ofdiatomaceous earth. The cake is washed with ether (3×50 ml). Thecombined filtrates are dried over magnesium sulfate and the volatilesevaporated in vacuo to afford a residue which is vacuum distilled togive 8.9 g of the desired product, BP 85°-87° C./10 mm

n₂₀ ^(D) 1.4458 [α]_(D) ²⁰ +23.2 (c 10, CH₃ OH). ¹³ C-NMR: 134.49(C-5),117.28(C-6), 62.69(C-1), 58.65(C-2), 55.12(C-3), 36.45(C-4).

Anal. Calc'd for C₆ H₁₀ O₂ : C, 63.13; H, 8.83 Found: C, 62.88; H, 8.19

EXAMPLE 4 Titanium (IV) difluorodiisopropoxide

To a stirred mixture of 37.4 g of benzoyl fluoride in 100 ml of hexane,while cooling in a 20°-25° C. bath is added dropwise 28.4 g of titanium(IV) isopropoxide. The reaction proceeds with an increase intemperature. A white solid forms, which is filtered in an inertatmosphere, then dried under vacuum to afford 13.6 g of the desiredproduct as a white fine powder.

EXAMPLE 5 2R,3S-3-Fluorohex-5-en-1,2-diol

A mixture of 13.6 g of titanium (IV) difluorodiisopropoxide in 180 ml ofdry toluene is heated to reflux with stirring in a 120° C. oil bath. Asolution of 5.8 g of 2R,3R-epoxyhex-5-en-1-ol in 10 ml of dry toluene isadded dropside to the refluxing reaction mixture. The bath is removedfollowing complete addition and stirring continued while the temperaturelowers to 25°-30° C. A 15 ml volume of saturated sodium bicarbonate isadded with vigorous stirring. Stirring is continued over 2 hours and thepH is neutral to slightly alkaline. Additional saturated sodiumbicarbonate added as needed to adjust the pH. The reaction mixture isfiltered through diatomaceous earth, and the cake washed with acetone.The combined filtrates are dried with MgSO₄ and the volatiles removed invacuo. The residue is purified by chromatography on silica gel byelution with 50:1 chloroform-isopropyl alcohol to afford 3.4 g of thedesired product as a white crystalline solid, m.p. 37°-38° C. TLC (9:1chloroform-isopropyl alcohol) R_(F) =0.41.

¹³ C-NMR: 134.85(d, J_(C-F) 3.5Hz, C-5), 117.62(C-6), 93.52(d, J_(C-F)171.6Hz, C-3), 73.30(d, J_(C-F) 23.1Hz, C-2), 63.33(d, J_(C-F) 5.5Hz,C-1), 35.98(d, J_(C-F) 21.1Hz, C-4).

Anal. Calc'd for C₆ H₁₁ O₂ F: C, 53.72; H, 8.27; F, 14.17 Found: C,53.92; H, 8.01; F, 13.28.

EXAMPLE 6 Methyl-3-fluoro-2,3-dideoxy-α, β-D-erythropentofuranoside

A solution of 1.5 g of 2R,3S-3-fluorohex-5-en-1,2-diol is dissolved in150 ml of methyl alcohol and cooled to -60°--70° C. Oven dried ozone isbubbled through the reaction mixture for 3 hours. The reaction mixtureis allowed to warm to 0° C. and 0.05 g of palladium-on-carbon added.While stirring 250 ml of hydrogen is absorbed. The reaction mixture isfiltered and 1 ml of 10% HCl in methyl alcohol added. When the reactionis complete as shown by TLC (10:1 chloroform-methanol), the reactionmixture is neutralized with dry potassium carbonate, filtered andevaporated to give 1.0 g of the desired product as a mixture.

¹³ C-NMR: 106.27(C-1,β); 105.84(C-1,α), 95.55(d, J_(C-F) 175.6Hz,C-3-β), 94.58(d, J_(C-F) 177.6Hz, C-3-α), 86.31(d, J_(C-F) 22.6Hz,C-4-β), 85.51(d, J_(C-F) 23.6Hz, C-4-α), 63.15(d, J_(C-F) 10.0Hz,C-5-β), 62.44(d, J_(C-F) 9.6Hz, C-5-α), 55.40(-OMe-β), 54.68(-OMe-α),40.40(d, J_(C-F) 21.6Hz, C-2-β), 40.13(d, J_(C-F) 21.1Hz, C-2-α).

Anal. Calc'd for C₆ H₁₁ O₃ F: C, 47.99; H, 7.38; F, 12.65 Found: C,47.15; H, 6.69; F, 11.80

We claim:
 1. A process for preparing a compound of the formula: ##STR7##wherein M is selected from the group consisting of hydrogen and alkyl(C₁ -C₃), A is a nucleophilic substituent selected from the groupconsisting of halogen and moieties of the formula: ##STR8## and CNwherein R is selected from the group consisting of hydrogen, branchedand unbranched alkyl (C₁ -C₄) and phenyl; which comprises:(a) reacting acompound of the formula: ##STR9## wherein X is selected from chlorideand bromide, with propargyl alcohol to form hex-5-en-2-yn-1-ol; (b)reacting the product of step (a) with lithium aluminum hydride to form2,5-hexadien-1-ol; (c) reacting the product of step (b) in the presenceof diisopropyl-D-tartrate to form 2R,3R-epoxyhex-5-en-1-ol; (d) reactingthe product of step (c) with a suitable reagent having the nucleophilicsubstituent A as defined hereinabove, to form a compound of the formula:##STR10## (e) reacting the product of step (d) with ozone followed bycatalytic reduction with hydrogen over palladium-on-carbon andrecovering a compound of the formula: ##STR11##
 2. A process accordingto claim 1, wherein the suitable reagent of step (d) has the formula:

    Ti(OR').sub.n A.sub.4-n

wherein n is defined as an integer from 1 to 3; R' is selected frombranched and unbranched alkyl (C₁ -C₄) and A is selected from the groupconsisting of F, Cl, Br, I, moieties of the formula: ##STR12## and CNwherein R is selected from hydrogen, branched and unbranched alkyl (C₁-C₄) and phenyl.
 3. A process according to claim 2 wherein R' is definedas isopropyl, n is 2 and A is fluorine.
 4. A process according to claim2 wherein R' is defined as isopropyl, n is 1 and A is fluorine.
 5. Aprocess according to claim 2 wherein R' is defined as isopropyl, n is 1and A is --N₃.
 6. A process for preparing a compound of the formula:##STR13## wherein M is selected from hydrogen and alkyl (C₁ --C₃), A isa nucleophilic substituent selected from the group consisting ofhalogen, moieties of the formula: ##STR14## and CN wherein R is selectedfrom hydrogen, branched and unbranched alkyl (C₁ -C₄) and phenyl; whichcomprises:(a) reacting a compound of the formula: ##STR15## wherein X isselected from chloride and bromide with propargyl alcohol to formhex-5-en-2-yn-1-ol; (b) reacting the product of step (a) with lithiumaluminum hydride to form 2,5-hexadien-1-ol; (c) reacting the product ofstep (b) in the presence of diisopropyl-D-tartrate at -30° C. to -20° C.for 8-10 hours to form 2R,3R-epoxyhex-5-en-1-ol; (d) reacting theproduct of step (c) with a reagent of the formula:

    Ti(OR').sub.n A.sub.4-n

wherein n is an integer from 1 to 3; R' is selected from branched andunbranched alkyl(C₁ -C₄) and A is as defined above to form a compound ofthe formula: ##STR16## (e) reacting the product of step (d) with ozonefollowed by catalytic reduction with hydrogen over palladium-on-carbonand recovering a compound of the formula: ##STR17##
 7. A processaccording to claim 6 wherein R' is defined as isopropyl, n is 2 and A isfluorine.